We have been conducting a comprehensive genotype-phenotype correlation study in patients with the WAGR (Wilms tumor, aniridia, genitourinary anomalies, mental retardation) syndrome, which is caused by heterozygous contiguous gene deletions of variable size in the chromosome 11p13 region. We had previously observed that haploinsufficiency for BDNF, the gene which encodes brain-derived neurotrophic factor, is associated with higher prevalence of childhood obesity and higher scores on a hyperphagia questionnaire. BDNF is widely expressed throughout the nervous system and plays an important role in neuronal development and synaptic plasticity. In animal studies, BDNF appears to function downstream of the leptin signaling pathway to regulate appetite and energy balance. Our findings support the role of BDNF in human energy homeostasis. During this past year, we have been conducting further studies to characterize the role of BDNF in neurocognitive function because Bdnf+/- mice are not only hyperphagic and obese, but also display learning deficits, behavioral abnormalities, and decreased thermal pain response. In a cohort of 31 patients with the WAGR syndrome, we observed that BDNF haploinsufficiency was associated with lower scores on a parent-completed questionnaire assessing behavior responses to injuries or illnesses considered painful to most people (p=0.03). These findings suggest that BDNF plays a role in human nociception. Studies are currently underway to examine detection and pain thresholds for hot and cold stimuli. Tests of cognitive and adaptive function, psychiatric symptoms, and autism spectrum diagnoses are also ongoing. We have also been studying patients with Prader-Willi syndrome (PWS), which is caused by a lack of paternally expressed genes on chromosome 15q11-13. Patients with PWS typically present with hypotonia and poor feeding in the neonatal period followed by marked weight gain and severe hyperphagia between the ages of 1-5 years. PWS is also associated with cognitive impairment and behavioral abnormalities. We conducted a pilot study comparing 13 children with PWS versus 13 age/sex-matched lean controls and 13 age/sex/body mass index (BMI)-matched obese controls. We observed that patients with PWS had lower serum BDNF compared to the lean controls (p=0.03) as well as the obese controls (p=0.01). Lower serum BDNF suggests insufficient central nervous system production of BDNF because BDNF in peripheral circulation is believed to reflect cerebral output of BDNF. Decreased BDNF may be a potential cause for the disordered satiety and morbid obesity associated with PWS. BDNF insufficiency may also contribute to the neurocognitive abnormalities observed in PWS. We are currently conducting a study in a larger cohort of patients with PWS (25 infants, 25 non-obese children, and 25 obese children) and 75 BMI-matched controls to confirm these findings and to examine possible associations between cognitive function and serum BDNF concentrations. Additional ongoing investigations include studies in patients with Bardet-Biedl syndrome (in collaboration with Dr. Biesecker) and Alstrm syndrome, ciliopathy disorders in which the associated obesity may be due to defects in leptin-receptor signaling. In collaboration with Dr. Swedo, we are conducting a study of the associations between single nucleotide polymorphisms of the BDNF locus, serum and cerebral spinal fluid BDNF concentrations, and cognitive function in children with ASD. In collaboration with Dr. Kleinman, we are also examining the association between BMI, BDNF genotype, and hypothalamic BDNF expression in cadaveric brain tissue from adults with sudden death.